It is now clear that treatment of certain solid and liquid tumors with targeted monoclonal antibodies (mAb) can improve clinical outcome for many patients. It is also clear that in many instances this mAb therapy requires participation from the innate immune system. Nonetheless, tumors themselves exploit innate immune tolerance so as to weaken effective participation by the latter, thereby contributing to the fact that mAb therapy is still not curable today. In this competing renewal application we hypothesize that a better understanding of how the tumor exploits innate immune effector cell tolerance will lead to novel therapeutic options that largely reverse this process and enhance mAb therapy of cancer. To achieve this Project 1 (PI: J Byrd) plans to disrupt human B cell signaling in chronic lymphocytic leukemia with two novel compounds, examine innate immune effector cell function, and move to the clinic combining these agents with mAb B cell therapy; Project 2 (PI: S Tridandapani) will explore negative regulators of human monocytes / macrophage Fc? receptor signaling, as well as immune activators that reverse such negative regulators in order to improve antibody dependent cellular cytotoxicity (ADCC) of both liquid and solid tumors. Project 3 (PI: M Caligiuri) examines the mechanisms by which human natural killer (NK) cells acquire Fc?Rlll, and characterizes negative regulators of NK ADCC. Two clinical trials will then inhibit this negative signaling in order to enhance NK ADCC against lymphoma and NK cytotoxicity against multiple myeloma; Project 4 (PI: W Carson) examines the mechanism by which myeloid derived suppressor cells suppress innate effector cell ADCC, and explores different mechanisms to deplete these suppressor cells in order to enhance ADCC in the laboratory and in the solid tumor clinic. These four projects are served by the unique resources provided by Core A (Administration), Core B (Biostatistics) and Core C (Mouse Modeling and Animal Development). For the past 4.5 years, investigators within this P01 have published 51 collaborative manuscripts and have accrued 815 patients to clinical trials emanating from this P01. The next 5 years of work will result in improved clinical outcome of cancer patients undergoing with mAb therapy.